It has long been recognized that there is a need for agents which can improve or enable the permeability of non-lipophilic bioactive substances through biomembranes. In particular it would be advantageous to have agents that permit the reversible or transient permeabilization of biomembranes, such that bioactive molecules can be transported into cells or organs that are not normally accessible to these molecules without adversely affecting the viability of the cells. By way of example, the transport of nucleic acids and many other non-lipophilic substances is hampered by the lipophilic barrier that constitutes the cell membrane. There is an even greater need for agents that would enable therapeutic molecules to cross the lipophilic barrier that constitutes the blood brain barrier.
In the normal situation the central nervous system (CNS) is separated by a barrier from the general circulation, thereby permitting rigorous control of the microenvironment required for complex neural signaling. In certain pathological situations this blood brain barrier (BBB) interferes with the transport of therapeutic substances into the brain, thus hampering treatment of central nervous system lesions, including tumors, infections, abscesses and degenerative diseases.
The BBB maintains the homeostatic environment of the brain so that it can function irrespective of fluctuations in the systemic concentrations of compounds in the body. Moreover, it protects the brain from toxic agents and degradation products present in the circulatory system. Paradoxically, this barrier, which normally protects the brain, may be the cause for inefficient drug delivery into the brain, though in the pathological situation drug availability is crucial.
Molecules that show high therapeutic value in vitro and ex vivo in treatment of malignant infections and genetic diseases of the central nervous system are frequently found to be inactive in-vivo. This effect is due to insufficient access of the agent to the diseased target. Treatment of brain tumors is therefore problematic and the patients have poor prognoses. The same diminished effect can be seen in treatment of acute cerebral bacterial and viral infections, as well as with neurodegenerative and enzyme-deficiency diseases, such as Parkinson's disease, Huntington's chorea and Tay-Sachs disease.
Theoretically, the bioavailability problem presented above can be dealt with in several ways. The problem of delivering water soluble compounds, and in particular anticancer drugs, can be overcome by altering the biophysical characteristics of the drug. The permeability of a drug depends on its lipophilicity; thus, increasing the lipophilic nature of the compound may increase the therapeutic effect. Modification of a hydrophilic drug with hydrophobic groups such as alkyl or aromatic groups is a common way to improve their bioavailability. However, not all drugs maintain their therapeutic value after chemical modification.
Another strategy for attacking the problem of BBB impermeability is to alter the BBB itself, to enable transportation of the therapeutic substance into the brain (reviewed by Abbott and Romero, Molecular Medicine Today, March 1996, pp. 106-113). The most conmmon method of opening the BBB is by osmotic treatment. Mannitol is in clinical use as an agent for osmotic modification of the BBB. It was shown that chemotherapy administrated after barrier opening results in enhanced drug entry to both brain-tumor and brain, however, the studies also showed evidence that osmotic BBB modification causes complications. The primary problems include clinical manifestation of stroke, seizures, immunological reaction and ocular toxicity. Moreover, the osmotic treatment affects BBB opening for a very short period (Greig in Implications of the Blood-Brain Barrier and its Manipulation. Vol. 1, pp. 311-367, Neuwelt, E. A. ed., Plenum Press, N.Y., 1989).
A variety of other treatments have also been disclosed that increase permeability of the blood brain barrier including: the use of bradykinin agonists (WO 91/16355 of Alkermes) and certain other peptides (WO 92/18529 of Alkermes); use of bacterial cell wall fragments (WO 91/16064 of the Rockefeller Univ.) or the use of antibody to Bordetella pertussis filamentous haemagglutinin or brain endothelial x-molecule (WO 92/19269 of the Rockefeller Univ.). Certain fatty acids such as oleic acid have also been reported to reversibly open the BBB (Sztriha and Betz, Brain Res. 336, 257-262, 1991).
It has also been shown that valproic acid and other short chain fatty acids have membrane disordering potency and it was proposed that this activity might be correlated with the known sedative and anti-convulsant activity of these compounds (Perlman and Goldstein, Mol. Pharmacol. 26, 83-89, 1984).
The usefulness of methods for reversibly increasing the permeability of the blood brain barrier prior to administration of diagnostic reagents (U.S. Pat. No. 5,059,415 of the Oregon Health Sci. U.) or therapeutic reagents (WO 89/11299 of the Oregon Health Sci. U.) have been disclosed.
Known compositions for the permeabilization of biological membranes have not gained widespread acceptance in the medical community due to their adverse side effects or to their very short duration of action. Clearly, there is an unmet medical need for less toxic treatments with longer duration of action that will enable known effective drugs or diagnostic reagents to penetrate into the brain.